This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal of this subproject is to identify the impact of maternal sleep apnea-associated intermittent hypoxia on white matter development in offspring CNS. The study will focus on investigating the pathophysiological changes in oligodendroglial and axonal development elicited by maternal intermittent hypoxia exposure, and exploring the long-term consequences in the developing mice. Three aims are proposed to characterize the molecular and cellular mechanisms underlying IH-mediated white matter injury due to maternal OSA-related IH exposure: aim 1: to examine OL generation, proliferation, and differentiation in mouse forebrain and spinal cord at different embryonic stages following IH exposure during gestation (1st-2nd year);aim 2: to determine consequences of IH exposure on myelin-forming process and myelin architecture in developing and adult mice, as well as local effects on axonal development that maybe induced or deteriorated by myelin deficit (2nd-3rd year);aim 3: to explore signaling molecules invovled in IH-mediated white matter injury occurring in maternal sleep apnea during pregnancy (2nd -4th year). In our previous FY 2009 report, a mouse neonatal model of IH insult during the time window (P2 to P10) that is equivalent to the human 3rd trimester has been developed, because 1) clinical retrospective studies indicated that most of maternal OSA occurs in the last gestational period with severe symptoms;2) oligodendrocyte maturation, myelination, axon sprouting, and synapse formation initiate from the late second and early third trimesters of pregnancy, suggesting that maternal OSA in the 3rd trimester may result in much severe sequelae in offspring white matter. Our preliminary data showed that differentiation of oligodendrocyte, expression of myelin-related proteins, and syntheses of neurofilaments were significantly inhibited in IH-exposed developing mice. Based on this model, oligodendroglia and axon development has been intensively investigated in the past year. We found that IH induced hypomyelination in corpus callosum, striatum, fornix and cerebellum, but not pons or spinal cord during critical phases of central nervous system (CNS) development. IH elicited alterations in myelin-forming processes were reflected by decreased expression of myelin proteins including MBP, PLP, MAG and CNPase, suggesting arrested maturation of oligodendrocytes. Ultra-structural abnormalities were apparent in the myelin sheath and axon. Immature oligodendrocytes were more vulnerable to neonatal IH exposure than developing axons, suggesting that hypomyelination may contribute, at least partially, to axonal deficits. Insufficient neurofilament (NF) synthesis with anomalous components of NF subunits, [unreadable]-tubulin and MAP2 isoforms indicated immaturity of axons in IH-exposed mouse brains. In addition, down-regulation of Synapsin I, Synaptophysin and Gap-43 phosphorylation suggested a potential stunt in axonogenesis and synaptogenesis. The region-selective and complex impairment in brain white matter induced by IH was further associated with electrophysiological changes that may underlie long-term neurobehavioral sequelae.